Peter Borchmann1, Heinz Haverkamp2, Andreas Lohri3, Ulrich Mey4, Stefanie Kreissl5, Richard Greil6, Jana Markova7, Michaela Feuring-Buske8, Julia Meissner9, Ulrich Dührsen10, Helmut Ostermann11, Ulrich Keller12, Georg Maschmeyer13, Georg Kuhnert14, Markus Dietlein14, Carsten Kobe14, Hans Eich15, Christian Baues16, Harald Stein17, Michael Fuchs5, Volker Diehl18, Andreas Engert5. 1. Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany. Electronic address: peter.borchmann@uni-koeln.de. 2. Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany. 3. Cantonal Hospital Baselland, Liestal, Switzerland; Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland. 4. Cantonal Hospital Graubuenden, Chur, Switzerland; Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland. 5. Department of Internal Medicine I, University Hospital of Cologne, Cologne, Germany; German Hodgkin Study Group, Cologne, Germany. 6. Third Medical Department, Paracelcus Medical University, Salzburg, Austria. 7. University Hospital Kralovske Vinohrady, Third Faculty of Medicine, Charles University, Prague, Czech Republic. 8. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany. 9. University Hospital of Heidelberg, Heidelberg, Germany. 10. Department of Hematology, University Hospital of Essen, Essen, Germany. 11. Department of Internal Medicine III, Klinikum Großhadern, Munich, Germany. 12. Department of Internal Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. 13. Department of Internal Medicine, Haematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany. 14. Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany. 15. Department of Radiotherapy, University Hospital of Muenster, Muenster, Germany. 16. Department of Radiotherapy, University Hospital of Cologne, Cologne, Germany. 17. Berlin Reference Center for Lymphoma and Haematopathology, Berlin, Germany. 18. German Hodgkin Study Group, Cologne, Germany.
Abstract
BACKGROUND:Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPPescalated) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. METHODS: In this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPPescalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPPescalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPPescalated (BEACOPPescalated group) or BEACOPPescalated plus rituximab (R-BEACOPPescalated group). PET-2 was assessed using a 5-point scale with 18FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPPescalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPPescalated (day 0 and day 3 in cycle 4, day 1 in cycles 5-8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. FINDINGS:Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPPescalated group (n=220) or the R-BEACOPPescalated group (n=220). With a median follow-up of 33 months (IQR 25-42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0-95·7) for patients in the BEACOPPescalated group and 93·0% (89·4-96·6) for those in the R-BEACOPPescalated group (difference 1·6%, 95% CI -4·0 to 7·3; log rank p=0·99). Common grade 3-4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPPescalated group vs 211 [96%] of 220 patients in the R-BEACOPPescalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPPescalated group and ten (5%) of 220 in the R-BEACOPPescalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPPescalated group and three (1%) in the R-BEACOPPescalated group, all of them due to infection. INTERPRETATION: The addition of rituximab to BEACOPPescalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. FUNDING: Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.
RCT Entities:
BACKGROUND: Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPPescalated) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. METHODS: In this open-label, international, randomised, phase 3 study, we recruited patients aged 18-60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPPescalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPPescalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPPescalated (BEACOPPescalated group) or BEACOPPescalated plus rituximab (R-BEACOPPescalated group). PET-2 was assessed using a 5-point scale with 18FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPPescalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPPescalated (day 0 and day 3 in cycle 4, day 1 in cycles 5-8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. FINDINGS: Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPPescalated group (n=220) or the R-BEACOPPescalated group (n=220). With a median follow-up of 33 months (IQR 25-42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0-95·7) for patients in the BEACOPPescalated group and 93·0% (89·4-96·6) for those in the R-BEACOPPescalated group (difference 1·6%, 95% CI -4·0 to 7·3; log rank p=0·99). Common grade 3-4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPPescalated group vs 211 [96%] of 220 patients in the R-BEACOPPescalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPPescalated group and ten (5%) of 220 in the R-BEACOPPescalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPPescalated group and three (1%) in the R-BEACOPPescalated group, all of them due to infection. INTERPRETATION: The addition of rituximab to BEACOPPescalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. FUNDING: Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.
Authors: Paolo Strati; Michelle A Fanale; Yasuhiro Oki; Francesco Turturro; Luis E Fayad; Nancy L Bartlett; Douglas E Gladstone; Yvette L Kasamon; Carol S Portlock; Wyndham H Wilson; Andre Goy; Anas Younes; Hun Ju Lee Journal: Haematologica Date: 2018-09-06 Impact factor: 9.941
Authors: Chul S Ha; Michael LeBlanc; Heiko Schöder; Chelsea C Pinnix; Nancy L Bartlett; Andrew M Evens; Eric D Hsi; Lisa Rimsza; Michael V Knopp; Jun Zhang; John P Leonard; Brad S Kahl; Hongli Li; Sonali Smith; Louis S Constine; Jonathan W Friedberg Journal: Leuk Lymphoma Date: 2020-05-26
Authors: David J Straus; Sin-Ho Jung; Brandelyn Pitcher; Lale Kostakoglu; John C Grecula; Eric D Hsi; Heiko Schöder; Leslie L Popplewell; Julie E Chang; Craig H Moskowitz; Nina Wagner-Johnston; John P Leonard; Jonathan W Friedberg; Brad S Kahl; Bruce D Cheson; Nancy L Bartlett Journal: Blood Date: 2018-07-26 Impact factor: 22.113
Authors: Jasmin Mettler; Horst Müller; Conrad-Amadeus Voltin; Christian Baues; Bernd Klaeser; Alden Moccia; Peter Borchmann; Andreas Engert; Georg Kuhnert; Alexander E Drzezga; Markus Dietlein; Carsten Kobe Journal: J Nucl Med Date: 2018-06-07 Impact factor: 10.057